Dr. Clark Chen, MD, PhD, Chief of Stereotactic and Radiosurgery and Vice-Chairman of Neurosurgery at UC San Diego Health System
Related Story: Cancer Treatment In Clinical Trials At UC San Diego
CAVANAUGH: An innovative approach to treat brain cancer is in clinical trials at the UC San Diego Moors cancer center. The trial is one of the first in the world to combine gene therapy with real-time MRI imaging. That means doctors can deliver the treatment directly into the tumor. Doctors hope that previously untreatable brain cancers can be helped by this new procedure. I'd like to welcome my guest Dr. Clark Chen, chief of stereo tactic and brain surgery and vice chair of neurosurgery at the UC health system.
CHEN: Thank you for having me.
CAVANAUGH: What type of brain tumor is this clinical trial targeting?
CHEN: It's targeting the most common form of brain cancer, called glioblastoma. This is a devastating cancer. The average survival for a patient with this tumor is essentially about 14 months. What's devastating about this disease is that it has the capacity to take away those qualities that we consider human. Our ability to talk, hear, think, feel. And as the tumors progress, the patients gradually lose these abilities and really suffer a diminishment in their quality of life. So this is really a devastating disease, and it's a disease that's taken away many of our intellectual leaders of our time. For instance, Senator Kennedy expired from this disease about a year after he was diagnosed.
CAVANAUGH: Now, as you say, are this is one of the deadliest forms of brain cancer. What makes it so difficult to treat? Are these tumors, first of all, are they inoperable?
CHEN: That's a very good. There's several reasons why this tumor is so difficult to treat. And one of the reasons is that rather than clustering in one area in the brain, by the time the diagnosis is made, typically the tumor has spread to multiple areas in the brain. That's No. 1. The second reason is that the brain is such an important organ in our body that we have involved specific ways in which we protect the brain from various harmful chemicals. That's normally good except that in the case of a brain tumor patient, the blood brain barrier also prevents the drug from getting into the brain. And that means it's estimated that only about 1% of all the drugs that we have today could get into the brain.
CAVANAUGH: I see.
CHEN: So effectively, if you imagine treating cancer as a chess game where you make a move and a cancer makes a counter-move, the number of moves we have against a cancer is extremely limited result of this blood brain barrier.
CAVANAUGH: I called this particular therapy, this procedure that you're trying out as ingenious. And I think it is. I wish you would tell us about the gene developed by Technogen, that you want to get inside the tumor. It's sometimes called a suicide gene. What is it supposed to do?
CHEN: That's a great question, and it is a very clever construct. Of the construct was equip developed by Dr. Harry Gruber who was a former faculty at UCSD. This virus that we're putting into the patient's tumor produces a particular enzyme that converts a completely benign drug into chemotherapy. So what happens is we inject the virus into the tumor, and the tumor is engineered only to replicate in the tumor. So this virus is not present anywhere else in your body. As the patient takes the antifungal medicine which percolates throughout the entire body including the brain. That drug is benign until it meets the tumor cells as the virus. And there and only there the drug is converted into a chemotherapy, and that in turn destroys the tumor. So by putting the virus into the tumor, the tumor becomes suicidal as it contacts this drug. And the beauty of this therapy is one of the major drawbacks of chemotherapy is that it's given systematically. So that means virtually every cell in your body is exposed to its effect of the drug. Whether that's good effect or side effects. And the beauty of this treatment paradigm is that we generate chemotherapy only at the site of the tumor, so we protect the patients from the potential side effect ofs of the chemotherapy.
CAVANAUGH: So the gene itself doesn't kill the cancer, but it makes it possible for the second drug that the patient takes orally to change to chemotherapy only in that targeted area in the tumor.
CHEN: That's exactly right.
CAVANAUGH: That's amazing! Now, the second crucial part of this new therapy is the MRI imaging. How does that work?
CHEN: Well, in order for us to address the blood brain barrier issue, we need to visualize whether or not the drug even gets into the brain. Remember I told you only about 1% of the drug gets into the brain. And so if a patient takes a drug and fails therapy, until now it is not possible for us to know whether it's because the drug is insufficient to kill the tumor or if it never got there in the first place. So by using real-time MRI where we could visualize exactly where the virus is delivered to, we can then study the consequences of that. For instance, if the tumor grew back in the area where we know there's virus, then we know we have our work cut out for us in terms of developing better viruses. On the other hand, if the tumor grows elsewhere, we will focus our energy on developing technology that will allow us to deliver viruses to those places. So fundamentally the MRI technology helps us in terms of what the next rational step is in treating this cancer.
CAVANAUGH: And how do you actually see this on the MRI? Is there something that happens in the tumor? How do you know that this suicide gene, this drug, is actually entering the tumor itself?
CHEN: That's a very good question. There are specific studies that can be done and are being done where you could actually insert what's called a microdialysis probe that can measure the chemicals in the tumor, and you could actually measure how much of the drug is produced in the tumor. And that is currently being done.
CAVANAUGH: Now, can you describe what this process actually looks like for our listeners? The patient apparently is inside the MRI machine. So how do you actually deliver the gene therapy?
CHEN: The MRI machine is engineered such that the patient could be rolled in and out of essentially a doughnut-like structure. And what happens is we will take images of the patient as patient's in the MRI. Most of the surgical manipulation considers outside. So the patient is rolled out of the MRI, and after the surgical procedure part is done, we get that back in. And there's specific controllers that allow us to remote control the trajectory of our delivery catheter. And one of the beauties of this technology from a surgeon's perspective is that I can see in real-time exactly where the catheter is so that I could avoid all the dangerous structures that we don't want to intersect with our trajectory. And in that way, we could minimize the danger of the procedure. And in fact I'm happy to say that of all the patients who have undertaken this procedure. They've all been discharged the very next day and resumed their daily activities thereof.
CAVANAUGH: Wow. Now, how long does this procedure take? It sounds incredibly complex.
CHEN: It is. And the procedures we've done typically last on the order of 6-8 hours.
CHEN: Does a patient have to undergo more than one of these procedures?
CHEN: Well, so far the procedure itself is designed as a stand-alone, so that we infuse the virus in its entirety in one surgical session. It's conceivable in the future, if the patient for instance -- where the tumor is injected, the tumor resolved, and another tumor pops up elsewhere, it's entirely conceivable that the patient go undergo a second surgery.
CAVANAUGH: Has this procedure actually worked to kill a brain tumor caused by this particular type of cancer?
CHEN: That's a really good question. I think we are in clinical trial because we have very convincing data in animal models where this virus works beautifully, exquisitely! Mouse have been cured of brain tumors using this technology. But its effectiveness in human beings remains a question that we need to address. But I am optimistic of the patients I've treated so far. I'm seeing very promising results.
CAVANAUGH: In that tumors are shrinking?
CHEN: The tumors are responding and the patients are doing well. That said, we have to be very cautious about interpreting these results. These patients are a very highly selected subset of patients. So the data in terms of whether or not this therapy will work in human patients remains unknown. But that said, I think what is really amazing about this technology is it's not limiting to just the virus. Someday we should be able to inject just about any drugs into brain tumors. And what that means is that expands the number of chess moves we have against the cancer. And hopefully by expanding the number of options that we have against cancer, we could eventually move meaningfully toward a cure.
CAVANAUGH: Every once in a while, know when there are clinical trials, there are people selected for those trials who are very, very ill. And this is perhaps their last hope. Is that the subset of patients that you selected for this clinical trial?
CHEN: Well, this clinical trial actually has specific clinical cutoffs in terms of how well the patients are doing. We have a spectrum of patients who are doing well and who are deteriorating. It's actually a fairly good representation. But that said, this is what we call a phase 1 study. And that's really designed to look at the safety and tolerability of the procedure. We really have to be very cautious, and more work must be done to establish the efficacy.
CAVANAUGH: Now, how many hospitals are experimenting with this particular therapy?
CHEN: There's only been three centers in the world that has successfully completed this procedure. And based upon those experiences, including our own, we believe that this is a safe and easily tolerated procedure.
CAVANAUGH: Is the glioblastoma the only kind of brain tumor that this therapy might help?
CHEN: We have also expanded this to another form of brain cancer called Endo plastic blasto sight onlia. That is slightly different, and the patients do live a little bit longer. That said, almost all these tumors eventually progress to glioblastoma, at which point they're facing the same challenges as the glioblastoma patients. So the subsets are the patients who are afflicted with glioblastoma and Endo plastic.
CAVANAUGH: You mentioned when a patient is treated with chemotherapy, there are sometimes devastating side effects. Are there any side effects that your patients have experienced with this therapy?
CHEN: Well, much to my pleasant surprise, thus far I've not seen adverse events in my particular patients. But that said, I think that we need to expand the sample size. Most side effects do not occur in the first ten, 15 patients. We're doing what's called dose escalation. So for after every three patients, we're increasing the dose of the gene therapy in order to obtain the optimal dose. So thus far, the therapy appears absolutely safe.
CAVANAUGH: And how many patients have you treated with this therapy?
CHEN: In total, almost 13 patients at UCSD. Of those, only two have undergone the MRI-guided procedure.
CAVANAUGH: Only two!
CHEN: That's right. This is really at the infancy of this procedure. And if this procedure proves to be safe and efficacious, I believe this can fundamentally change how we treat brain cancers in the future.
CAVANAUGH: We're all hoping for the best for your patient, of course. But I wonder what else you hope to learn from this clinical trial.
CHEN: There's a lot of added studies and knowledge that can be acquired. For instance, right now, we're visualizing the delivery of the virus in real-time. And we know exactly where they were at the time of injection. In principle, the viruses could diffuse away from those sites. So there are studies to look at whether or not the viruses stay where they are. There are studies to look at whether or not the virus gets into the fluids that cover the brain. There's studies to look at the optimal dosing for getting this virus. There's studies that's looking at molecular features, what is it about the tumor that allows it to respond this therapy or not? So there's a variety of investigative studies that are tacked onto this trial. And I really hope, and I believe we will, learn a lot more about this disease through this clinical trial.
CAVANAUGH: Doctor Chen, it's been fascinating, and I wish you the best of luck.
CHEN: Thank you for having me here. I'm a big fan of the show, and this means a lot to me.
CAVANAUGH: Thank you so much.
CHEN: Thank you.